Langerhans cells (LC) represent a small subpopulation of the mammalian epidermis. Though morphologically well characterized the functional role of these cells is still unknown. The previous hypothesis that LC are functionally related to macrophages is strongly supported by the recent finding that human and guinea pig epidermal LC express Fc-IgG receptors, C3 receptors and Ia antigens. In this study we investigated whether guinea pig LC can mediate the same immunologic functions as Ia-bearing macrophages. LC-enriched (LC-e) and LC-depleted (LC-d) epidermal cells were prepared by separation of Fc-IgG rosetting epidermal cells on density gradients. The percentage of LC ranged from 18–35% in the enriched fraction and from 0.2–0.5% in the depleted fraction as evaluated by histochemical staining techniques. Virtually all the Ia activity was restricted to the LC-e population as determined by immunoprecipitation experiments.